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N-Acyl Amino Acids (Elmiric Acids): Endogenous Signaling Molecules with Therapeutic Potential

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N-Acyl Amino Acids (Elmiric Acids): Endogenous Signaling Molecules with Therapeutic Potential Molecular Pharmacology Fast Forward. Published on November 14, 2017 as DOI: 10.1124/mol.117.110841 This article has not been copyedited and formatted. The final version may differ from this version. MOL #110841 1 MINIREVIEW N-Acyl amino acids (Elmiric Acids): endogenous signaling molecules with therapeutic potential Sumner H. Burstein Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605 Downloaded from molpharm.aspetjournals.org at ASPET Journals on September 30, 2021 Molecular Pharmacology Fast Forward. Published on November 14, 2017 as DOI: 10.1124/mol.117.110841 This article has not been copyedited and formatted. The final version may differ from this version. MOL #110841 2 Running title. N-Acyl amino acids; endogenous signaling molecules Corresponding author: Sumner H. Burstein, Department of Biochemistry & Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605 [email protected] Phone: 508-856-2850 FAX: 508-856-2251 Number of of text pages, 26 Number of tables, 3 Downloaded from Number of figures, 4 Number of references, 60 Number of words in the: molpharm.aspetjournals.org Abstract, 220 Introduction, 742 Discussion, 6338 Abbreviations: COX, cyclooxygenase; FAAH, fatty acid amide hydrolase; GABA, γ- at ASPET Journals on September 30, 2021 aminobutyric acid; GPCR, G-protein coupled receptor; LXA4, lipoxin A4 ; LOX, 12,14 lipoxygenases; PGJ,15-deoxy-Δ -prostaglandin-J2 Molecular Pharmacology Fast Forward. Published on November 14, 2017 as DOI: 10.1124/mol.117.110841 This article has not been copyedited and formatted. The final version may differ from this version. MOL #110841 3 Abstract The subject of N-acyl amino acid conjugates has been rapidly growing in recent years, especially with regard to their analgesic and anti-inflammatory actions. The field is comprised of a large family of lipid signaling molecules whose importance is only now being fully realized. The most widely studied member is N-arachidonoyl glycine (NAGly), which differs structurally from the endocannabinoid anandamide (N- arachidonoyl ethanolamide) by a single oxygen atom and the two are metabolically related. Topics that are covered in this mini review are: biosynthetic pathways for N-acyl Downloaded from amino acids, receptors for N-acyl amino acids, physiological actions of N-acyl amino acids, pharmacological effects of N-acyl amino acids and molecular mechanisms believed to be responsible for their effects. On the subject of mechanisms, several molpharm.aspetjournals.org possibilities based on currently available information are proposed. Four putative pathways can be suggested. (1) Inhibition of FAAH induced increases anandamide or 2- AG levels, resulting in analgesic activity. (2) Binding to GPR18 initiating the production of anti-inflammatory eicosanoids. Specifically, the data suggest roles for 15-deoxy- 12,14 Δ -prostaglandin-J2 and lipoxin A4 both of which are potent inflammation-resolving at ASPET Journals on September 30, 2021 molecules. (3) Inactivation of T-type Ca(V)3 channels and (4) inhibition of the GLYT2 glycine transporter that would each produce analgesic effects. Also, the N-acyl amino acids do not bind to either cannabinoid or opioid receptors, thus reducing adverse actions and making them good templates for novel drug candidate molecules. Molecular Pharmacology Fast Forward. Published on November 14, 2017 as DOI: 10.1124/mol.117.110841 This article has not been copyedited and formatted. The final version may differ from this version. MOL #110841 4 I. Introduction. A class of N-acyl amino acids in which long chain fatty acids covalently coupled to amino acids by an amide bond are sometimes called elmiric acids and have emerged as an important family of endogenous signaling molecules (Bradshaw and Walker, 2005) that regulate pain and inflammation, (Burstein et al., 2007; Huang et al., 2001; Zurier and Burstein, 2016). The existence of these endogenous substances was first suggested in 19971 and later, synthetic examples were shown to exhibit anti- inflammatory and analgesic activity in mice (Burstein et al., 2000). Subsequent studies Downloaded from identified several naturally occurring N-acyl amino acids in rat brain extracts (Huang et al., 2001). Their actions include analgesia (Huang et al., 2001; Jeong et al., 2010; Vuong et al., 2008), anti-inflammatory effects (Burstein et al., 2007), selective inhibition molpharm.aspetjournals.org of cancer cell proliferation (Burstein and Salmonsen, 2008), vasodilation (Parmar and Ho, 2010), cell migration (McHugh et al., 2010; McHugh et al., 2012a) and calcium ion mobilization (Kohno et al., 2006; Ross et al., 2009). To date, about 70 naturally occurring members as well as several synthetic analogs of the N-acyl amino acid family have been identified (Burstein et al., 2007). These comprise various combinations of at ASPET Journals on September 30, 2021 amino acids linked to long-chain acids by an amide bond (Table 1). For most of these molecules, little is known about their biological activity. An earlier review covers some of these topics and includes the related acyl neurotransmitters (Connor et al., 2010); these were briefly updated in a later review (Burstein, 2014). Even though the N-acyl amino acids have been known for some time, their roles in cells have only recently been appreciated. They bear many similarities to anandamide, one of the important endocannabinoids, both in chemical structure and in biological activity. Moreover, they may be metabolically interrelated either directly or indirectly. It is of interest that the levels of N-acyl amino acids in rat brain are several fold higher than that of anandamide (Burstein, 2008). The first to be discovered1 and the most widely studied acyl amino acid conjugate, N-arachidonyl glycine (NAGly) is shown in Figure 1, and is found in rat brain, spinal cord, and other tissues where it occurs in amounts greater than the closely related endocannabinoid, anandamide Molecular Pharmacology Fast Forward. Published on November 14, 2017 as DOI: 10.1124/mol.117.110841 This article has not been copyedited and formatted. The final version may differ from this version. MOL #110841 5 (arachidonoyl ethanolamide) (Huang et al., 2001). A preliminary report suggested that NAGly possesses analgesic properties but lacks the psychotropic activity of the cannabinoid receptor 1 (CB1) active cannabinoids.1 It has been shown that NAGly does not bind to the cannabinoid CB1 or CB2 receptors (Sheskin et al., 1997), however, it appears to activate the orphan G-protein coupled receptor (GPCR), GPR18 (Kohno et al., 2006). Table 2 shows a list of some of the actions of NAGly. II. Biosynthetic Pathways for N-acyl amino acids. The biological origin of NAGly is not completely understood; however, two Downloaded from possible biosynthetic pathways have been proposed and data supporting the existence of each have been reported (Burstein et al., 2000; Huang et al., 2001). Using anandamide radiolabelled in the ethanolamine moiety, Burstein et al. (2000) showed molpharm.aspetjournals.org that Chang hepatocytes incubated with this precursor produced a radiolabelled peak that chromatographically co-migrated with NAGly in several thin layer chromatography systems. This suggested that NAGly may, under some conditions, be generated by oxidative metabolism of anandamide (Figure 2). A second pathway, shown in Figure 3, that involves condensation of arachidonyl CoA with glycine was proposed by Huang et at ASPET Journals on September 30, 2021 al. (2001), where the process is mediated by a subcellular rat brain preparation. To support this suggestion, they used deuterium labeled precursors and demonstrated the synthesis of deuterated NAGly by mass spectrometric analysis. Both pathways may operate, depending on the specific set of circumstances. Also, Bradshaw et al. reported evidence that FAAH plays a role in NAGly metabolism; however, such a role appears to be one of anabolism (Bradshaw et al., 2009). Additionally, their data suggest that anandamide may serve as a precursor for NAGly, which differs from anandamide only by the oxidation state of the carbon beta to the amido nitrogen. Other studies found that cytochrome c catalyzes the synthesis of NAGly from arachidonoyl coenzyme A and glycine in the presence of hydrogen peroxide. Hemoglobin and myoglobin, were much less effective in mediating the synthesis of NAGly as compared to cytochrome c (McCue et al., 2008). It was subsequently reported that cytochrome c also promotes the formation of N-arachidonoyl serine, N-arachidonoyl alanine, and N-arachidonoyl γ−aminobutyric acid from arachidonoyl CoA and the Molecular Pharmacology Fast Forward. Published on November 14, 2017 as DOI: 10.1124/mol.117.110841 This article has not been copyedited and formatted. The final version may differ from this version. MOL #110841 6 respective amino acids (McCue et al., 2009). Interestingly, it was discovered that arachidonoyl CoA and ethanolamine react spontaneously to form anandamide, independent of cytochrome c and hydrogen peroxide. Further evidence for the existence of the two pathways was recently reported (McHugh et al., 2012a). When d4 anandamide was incubated with HEC-18 endometrial cells, two isotopic forms of NAGly were isolated. The d4 anandamide product was labeled on the ethanolamine part of the structure. The incubation products were d0 - NAGly and d2 -NAGly. The first has to result from the general pathway shown in Figure Downloaded
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